This invention relates to newly identified polynucleotides, polypeptides encoded by them and to the use of such polynucleotides and polypeptides, and to their production. More particularly, the polynucleotides and polypeptides of the present invention relate to the hyaluronan synthase family, hereinafter referred to as HOEFC11. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides.
Hyaluronic acid (HA), an important constituent of extracellular matrix, is a linear polysaccharide of alternating glucuronic acid and N-acetyl glucosamine residues. It is synthesized by a membrane-bound enzyme hyaluronan synthase (HAS) and extruded into the extracellular space. Cloning of two human HAS (HAS 1 and HAS 2) has been reported very recently (K. Watanabe and Y. Yamaguchi, J. Biol. Chem. 271:22945-22948, 1996) (N. Itano and K. Kimata, Biochem. Biophy. Res. Communications, 222:816-820, 1996). HA synthesis is involved in many cellular functions such as migration, invasion, adhesion, transformation, proliferation and wound healing. HA synthesis has been shown to be induced by FBS, PDGF, EGF, IL-1, retinoic acid, IGF, TGF beta, etc. Increased HA production is: (a) a general phenomenon in various organs attacked by inflammatory cells, (b) implicated in tissue edema, (c) a characteristic of tissue remodeling and (d) a marker for early stage of extracellular matrix remodeling following vascular injury. Increased levels of HA have been reported in chronic renal failure, inflammatory diseases, cancer (prostate, mammary and other invasive tumors), aortas from diabetic patients, smaller airways of patients with acute alveolitis, transplantation edema in rejecting heart and kidney, myocardial ischemia, balloon injury, liver cirrhosis, wound healing and angiogenesis. Hyaluronidase (breaks down HA) is reported to be beneficial in limiting cellular damage during myocardial ischemia in rat, dog and man. This indicates that the hyaluronan synthase family has a established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of the hyaluronan synthase family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, chronic renal failure, inflammatory diseases, myocardial ischemia, cancer, rheumatoid arthritis, cirrhotic liver disease.
In one aspect, the invention relates to HOEFC11 polypeptides and recombinant materials and methods for their production. Another aspect of the invention relates to methods for using such HOEFC11 polypeptides and polynucleotides. Such uses include the treatment of chronic renal failure, inflammatory diseases, myocardial ischemia, cancer, rheumatoid arthritis, cirrhotic liver disease, among others. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with HOEFC11 imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate HOEFC11 activity or levels.